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Biomedical subjects

David Robertson

Publications and source records attributed to David Robertson.

At least 55 records · Page 3Linked to original sources
PubMed2004

Altered profile of baroreflex and autonomic responses to lower body negative pressure in chronic orthostatic intolerance.

BACKGROUND: Chronic orthostatic intolerance (COI) is a common and disabling autonomic syndrome of unclear pathophysiology. We tested the hypothesis that baroreflex and autonomic responses to graded lower body suction (LBNP, up to -40 mmHg) could be altered in COI patients. METHODS: Electrocardiogram (ECG), non-invasive arterial blood pressure and respiratory activity were measured during progressive LBNP (seven patients and seven volunteers). Lumped arterial baroreflex sensitivity (alpha index), and its arterial and cardiopulmonary components, were assessed by multivariate closed-loop analysis of RR interval and systolic arterial pressure (SAP) spontaneous variabilities and respiration. Monovariate spectral analysis of RR interval and SAP variability provided markers of autonomic regulation of the sinoatrial (SA) node and of vascular sympathetic modulation. RESULTS: Similar reductions in overall and cardiopulmonary baroreflex gain were observed in both groups in response to graded LBNP. In contrast, only controls demonstrated a selective increase in arterial baroreflex sensitivity, at low-grade LBNP. Clear increases in the low-frequency component of RR interval variability (LFRR) [and decreases in the high-frequency component of RR interval variability (HFRR), both in normalized units] were observed in controls with graded LBNP, while insignificant changes occurred in COI patients, who showed, conversely, exaggerated sympathetic vasomotor responses [as assessed by the low frequency component of SAP variability (LFSAP)]. CONCLUSIONS: Patients with chronic orthostatic intolerance show distinct signs of altered baroreflex and autonomic regulation of the SA node and of the vasculature in response to graded LBNP.

Adult↗
PubMed2004

Fear, black people and mental illness: a vicious circle?

The relationships between black communities and the mental health (MH) services are fraught. Paradoxically, black communities receive the MH services they don't want, but not the ones they do or might want. Black people mistrust and often fear services, and staff are often wary of the black community, fearing criticism, and not knowing how to respond, are fearful of black people, in particular, young black men. The situation is fueled by prejudice, misunderstanding, misconceptions and sometimes racism. The present paper describes the findings of a study to explore the issues in greater depth. The study was premised on a belief that there are 'circles of fear' which lead to poorer treatment of black communities. A purposive sampling approach was used to seek out groups and individuals in whom the 'circles of fear' were likely to be evident. The findings suggest that there are fears which impact negatively on the interaction between black communities and MH services. Two major themes emerged in this study, i.e. the sources of fear and the consequences of fear. Sources of fear included perceptions of MH services, attitudes to mental illness and diagnosis, and experiences of hospital care. The impact of fear included limited trust, limited engagement and delayed help-seeking behaviour. The study concludes that these fears mar the interactions between these communities and MH services, affect help-seeking behaviour adversely, and lead to restrictive and punitive interventions. Progress will only be made in breaking the 'circles of fear' if there is a systematic change in the experience of black services users at each point in the care pathway.

Adult↗
PubMed2003

Mechanisms of postspaceflight orthostatic hypotension: low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight.

Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only approximately 20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte beta(2)-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1). significantly smaller pressor responses to phenylephrine both before and after flight; 2). significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3). significantly greater norepinephrine release with tyramine on landing day; and 4). significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low alpha(1)-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.

Adrenergic alpha-Agonists↗
PubMed2003

Water ingestion as prophylaxis against syncope.

BACKGROUND: Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults. METHODS AND RESULTS: Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-table testing at 60 degrees for 45 minutes or until presyncope or syncope occurred. In their initial test, participants were randomized to either 16 oz (473 mL) of water drinking 5 minutes before tilt-table testing or tilt-table testing alone, with the alternative in a second test on a different day. During the first 30 minutes of tilt, 8 of 22 subjects without water experienced presyncope but only 1 of 22 who had ingested water (P=0.016). Water drinking attenuated the heart rate increase associated with tilt (P<0.001) while accentuating the increase in total peripheral resistance (P=0.012). The average time study participants tolerated head-up tilt was 26% longer after water (41.1+/-8.1 versus 32.6+/-14.3 minutes, mean+/-SD), with a pairwise mean difference of 8.5+/-14.0 minutes (95% CI, 2.3 to 14.7 minutes; P=0.011). CONCLUSIONS: Water enhances tolerance of upright posture. The effect of water is mediated by increased peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against vasovagal reactions in healthy subjects, such as those associated with blood donation.

Adolescent↗
PubMed2003

Effect of posture on blood and intraocular pressures in multiple system atrophy, pure autonomic failure, and baroreflex failure.

BACKGROUND: Intraocular pressure (IOP) may be partially under systemic vascular control. This study examined whether a correlation exists between blood and intraocular pressures in patients with autonomic dysfunction. METHODS AND RESULTS: Eleven patients with 3 types of confirmed autonomic dysfunction (multiple system atrophy, pure autonomic failure, and baroreflex failure) were compared with age- and gender-matched controls and had IOP, systolic blood pressure, diastolic blood pressure, heart rates, and calculated mean arterial pressures (MAP) and mean ocular perfusion pressures (MOPP) measured in the supine, sitting, and standing positions. Data were analyzed with a general linear model repeated-measures ANOVA. All pressures for patients showed a dramatic decline (P<0.001) from supine to standing (MAP -31+/-14 mm Hg; IOP -6+/-3 mm Hg; MOPP -25+/-14 mm Hg) compared with controls (MAP +4+/-7 mm Hg; IOP -1+/-2 mm Hg; MOPP +6+/-7 mm Hg). There was no significant change in heart rate from supine to standing for patients compared with controls (P=0.648). Within both the multiple system atrophy (n=5) and pure autonomic failure (n=4) groups, all initial pressures were similar to control pressures in the supine position, whereas patients with baroreflex failure (n=2) had higher mean pressures than respective controls in the supine position. CONCLUSIONS: In autonomic dysfunction, a large decrease in MAP correlated with a large decrease in IOP. These data suggest that the autonomic nervous system, perhaps through an influence on systemic blood pressure, has a significant role in IOP regulation.

Adult↗
PubMed2003

Effects of unilateral and bilateral carotid baroreflex stimulation on cardiac and neural sympathetic discharge oscillatory patterns.

BACKGROUND: Left and right carotid baroreflex afferents participate in generating the spontaneous variability of heart rate (HR), arterial pressure (AP), and muscle sympathetic nerve activity (MSNA), but the relative contribution of each side is unclear. Pathophysiological conditions unilaterally affecting carotid baroreceptor function might result in abnormal changes of HR, AP, and MSNA variability, thus markedly affecting prognosis. We tested the hypothesis that unilateral carotid baroreceptor perturbation might differentially affect HR, AP, and MSNA variability compared with stimulation of the opposite side. METHODS AND RESULTS: In 12 healthy volunteers, 4 sinusoidal neck suction procedures (0.1 Hz, from 0 to -50 mm Hg) were applied at the right, left, and combined right and left sides of the neck, in concordance or with phase opposition. Respiration was controlled at 0.25 Hz. Power spectrum analysis assessed the changes in the 0.1-Hz oscillatory component of the R-R interval, systolic AP (SAP), and MSNA variability induced by rhythmic baroreceptor stimulation. Mean R-R interval, SAP, and MSNA were unchanged during all procedures. The increase of the 0.1-Hz component of R-R and SAP variability during right and combined right and left carotid baroreceptor stimulation was greater than the changes induced by left-sided stimulation. The increase in the 0.1-Hz oscillatory component of MSNA variability was similar during all neck suction procedures. CONCLUSIONS: Right carotid baroreflex loading was as efficient as bilateral stimulation and more effective than left carotid suction in modulating R-R and SAP variability. There was no asymmetry in neural sympathetic discharge responses after single-sided carotid baroreceptor stimulation.

Adult↗
PubMed2003

Variations in the dopamine beta-hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy.

Norepinephrine (NE) is the major neurotransmitter of the sympathetic division of the autonomic nervous system (ANS). Recent findings of an association between human NE deficiency and variants at the dopamine beta-hydroxylase (DBH) gene [Kim et al., 2002] prompted us to investigate these markers in patients with autonomic disorders; 38 with orthostatic intolerance (OI), 26 with pure autonomic failure (PAF), and 39 with multiple system atrophy (MSA). Eighty-eight normal controls were included in this study. In contrast to NE deficiency, allele frequency and genotype distribution of the genetic variants showed no differences between autonomic disease patients and controls. In addition, no DBH mutation was found that distinguished autonomic disease patients from controls, suggesting that genetic variants of the DBH gene are not associated with the autonomic diseases OI, PAF, and MSA.

Autonomic Nervous System Diseases↗
PubMed2003

Three-dimensional interplay among the ligand-binding domains of the urokinase-plasminogen-activator-receptor-associated protein, Endo180.

Endo180, also known as the urokinase plasminogen activator receptor (uPAR)-associated protein (uPARAP), is one of the four members of the mannose receptor family, and is implicated in extracellular-matrix remodelling through its interactions with collagens, sugars and uPAR. The extracellular portion of Endo180 contains an amino-terminal cysteine-rich domain, a single fibronectin type II domain and eight C-type lectin-like domains. We have purified a soluble version of Endo180 and analysed it by single-particle electron microscopy to obtain a three-dimensional structure of the N-terminal part of the protein at a resolution of 17 A and reveal, for the first time, the interactions between non-adjacent domains in the mannose receptor family. We show that for Endo180, the cysteine-rich domain contacts the second C-type lectin-like domain, thus providing structural insight into how modulation of its several ligand interactions may regulate Endo180 receptor function.

Animals↗
PubMed2003

WT1 expression does not disrupt myogenic differentiation in C2C12 murine myoblasts or in human rhabdomyosarcoma.

WT1 encodes a tissue-specific transcription factor important in early mesenchymal differentiation. Altered expression or mutation of WT1 occurs in malignancies derived from such tissues. These include Wilms tumour, a paediatric kidney cancer that may show heterologous differentiation into primitive skeletal muscle, especially in tumours with WT1 mutation. A putative role for WT1 in inhibiting myogenesis has been suggested by transient transfection of C(2)C(12) myoblasts. However, using a more robust model of stable transfectants of C(2)C(12) expressing inducible WT1 isoforms, we found no inhibition of myogenic differentiation. We also investigated a possible role for WT1 in the disrupted myogenesis seen in rhabdomyosarcoma, a paediatric cancer resembling foetal skeletal muscle. WT1 expression levels measured by quantitative real-time reverse transcription polymerase chain reaction were low or absent in those tumours with a PAX-FKHR fusion gene characteristic of the alveolar subtype, and were higher in cases lacking these fusion genes. Overall, there was a weak positive correlation between expression of myogenic differentiation marker genes and WT1 levels. We conclude that expression of WT1 in C(2)C(12) cells and in rhabdomyosarcoma does not inhibit myogenic differentiation.

Animals↗
PubMed2003

Tau and 14-3-3 in glial cytoplasmic inclusions of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the presence of glial cytoplasmic inclusions (GCIs), which are comprised of fibrils of the protein alpha-synuclein (alpha-syn). Increasing evidence indicate that the formation of these lesions leads to cellular dysfunction and degeneration. The events that result in the formation of GCIs remain poorly understood. It is possible that changes in the cytoplasmic milieu, perhaps the aberrant expression of alpha-syn-interacting proteins, can promote the polymerization of alpha-syn. The presence of the microtubule-binding protein, tau, in GCIs has been reported in some studies, but these findings have not been consistent, and these studies were performed prior to the availability of the more sensitive methods of detecting GCIs using anti-alpha-syn antibodies. Recently, 14-3-3 proteins, putative alpha-syn-interacting partners, have been reported in Lewy bodies, which also are pathological inclusions comprised of alpha-syn. In this study the presence of tau and 14-3-3 proteins in GCIs of 21 patients with MSA was investigated. For the majority of cases, tau and 14-3-3 proteins were detected only in a subset of GCIs. In some cases none of the GCIs contained 14-3-3 or tau. When present in GCIs, tau was in a hypophosphorylated state as demonstrated with phosphorylation-specific antibodies. Alpha-syn fibrillogenesis without 14-3-3 or tau appears to be sufficient for GCI formation, although it is possible that the accumulation of multi-functional proteins, like 14-3-3, in GCIs contribute to the disruption of cellular homeostasis.

14-3-3 Proteins↗
PubMed2003

A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters.

The norepinephrine transporter (NET) mediates reuptake of norepinephrine released from neurons, and, as such, it is an important regulator of noradrenergic neurotransmission. Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). The presence of the hNET-A457P allele tracked with elevated heart rates and plasma NE levels in family members. hNET-A457P lacks >98% transport activity in several heterologous expression systems. In the present work, Western blot and biotinylation analyses performed in transiently transfected COS-7 cells revealed impairment in processing of hNET-A457P to the fully glycosylated form and a decrease in surface expression to approximately 30% of hNET-wild type (hNET-wt). Because the hNET-A457P mutation is carried on a single allele in OI subjects, we examined the influence of cotransfection of hNET-wt and hNET-A457P and found that hNET-A457P exerts a dominant-negative effect on hNET-wt uptake activity. Experiments to determine oligomerization as a potential mechanism of the dominant-negative effect demonstrated that hNET-A457P coimmunoprecipitates with, and diminishes surface expression of, hNET-wt. These results reveal that hNET-A457P causes a conformational disruption that interferes with transporter biosynthetic progression and trafficking of both the mutant transporter and hNET-wt. These results elucidate a molecular mechanism for the disrupted NE homeostasis and cardiovascular function evident in OI patients with the hNET-A457P mutation.

Amino Acid Substitution↗
PubMed2003

Neurovascular dissociation with paradoxical forearm vasodilation during systemic tyramine administration.

BACKGROUND: Despite the widespread use of tyramine as a pharmacological tool to assess the effects of norepinephrine release from sympathetic nerve terminals, its vascular effects are not adequately characterized. In particular, previous results indicate that intravenous tyramine produces little if any systemic vasoconstriction, suggesting that tyramine does not cause significant norepinephrine release from sympathetic nerves innervating peripheral vascular beds. To test this hypothesis, we determined the effects of intravenous tyramine on local forearm norepinephrine spillover and vascular resistance. METHODS AND RESULTS: Seven healthy subjects were studied with systemic and local forearm norepinephrine spillover and forearm blood flow at baseline, during systemic tyramine infusion, and after sympathetic stimulation induced by the cold pressor test. Tyramine infusion caused a significant increase in systemic and forearm norepinephrine spillover. The amount of norepinephrine released into the forearm by tyramine was similar to that caused by cold pressor stimulation, 0.15+/-0.05 versus 0.18+/-0.05 ng x dL(-1) x min(-1). As expected, forearm vascular resistance increased during the cold pressor test, but tyramine produced forearm vasodilation (4.5+/-1 versus -5+/-1 mm Hg x dL(-1) x min(-1), P<0.03) despite the increase in local norepinephrine spillover. In 6 additional subjects, plasma dopamine increased significantly during tyramine administration, from 11+/-3 to 662+/-105 pg/mL. CONCLUSIONS: Thus, systemic tyramine infusion evokes a significant increase in peripheral norepinephrine spillover, and this, paradoxically, is associated with local vasodilatation rather than vasoconstriction.

Adult↗
PubMed2003

VEGF expression is developmentally regulated during human brain angiogenesis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor working as an endothelial cell-specific mitogen and exerting a trophic effect on neurons and glial cells, both these activities being essential during central nervous system vascularisation, development and repair. The vascularisation of human telencephalon takes place by means of an angiogenic mechanism, which starts at the beginning of corticogenesis and actively proceeds up to the last neuronal migration, when the basic scheme of the vascular network has been drawn. Our study focused on VEGF during this critical developmental period with the aim of identifying the cells that express VEGF and of correlating the events of angiogenesis with the main events of cerebral cortex formation. The results show that in fetal human brain VEGF protein is located on multiple cell types, cells proper to the nervous tissue, neuroepithelial cells, neuroblasts and radial glia cells, and non-neuronal cells, endothelial and periendothelial cells. In these cells VEGF expression appears developmentally regulated and is correlated with angiogenesis, which in turn responds to the high metabolic demands of the differentiating neocortex.

Brain↗
PubMed2003

Traumatic events, migration characteristics and psychiatric symptoms among Somali refugees--preliminary communication.

BACKGROUND: Each refugee group experiences specific migration and resettlement experiences. There are no epidemiological data on risk factors for psychiatric symptoms among adult Somalis in the UK. METHODS: We interviewed a community sample of 180 Somalis. We assessed the relationship between symptoms of psychosis (BPRS), anxiety and depression (SCL-90) and suicidal thinking (BDI) and migration-related experiences such as traumatic events, immigration difficulties, employment and income. RESULTS: Anxiety and depression was incrementally more common with each pre-migration traumatic event (OR per trauma event = 1.31, 1.06-1.62, p = 0.01). Shortages of food, being lost in a war situation, and being close to death and suffering serious injury were each related to specific psychiatric symptoms. Suicidal thinking was more common among Somalis who were unemployed before migration and those using qat in the UK. CONCLUSIONS: War-related experiences, occupational status before migration and current Qat use are risk factors for psychiatric symptoms among Somali refugees.

Adult↗
PubMed2003

Understandings of environmental quality: ambiguities and values held by environmental professionals.

The terms used to describe and negotiate environmental quality are both ambiguous and value-laden. Stakeholders intimately and actively involved in the management of forested lands were interviewed and found to use ambiguous, tautological, and value-laden definitions of terms such as health, biodiversity, sustainability, and naturalness. This confusing language hinders public participation efforts and produces calls to regulate and remove discretion from environmental professionals. Our data come from in-depth interviews with environmental management professionals and other stakeholders heavily vested in negotiating the fate of forested lands. We contend that environmental science and management will be more effective if its practitioners embrace and make explicit these ambiguous and evaluative qualities rather than ignore and disguise them.

Attitude↗
PubMed2003

Hereditary dysautonomias: current knowledge and collaborations for the future.

The hereditary dysautonomias (H-Dys) are a large group of disorders that affect the autonomic nervous system. Research in the field of H-Dys is very challenging, because the disorders involve interdisciplinary, integrative, and "mind-body" connections. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for the first time in order to discuss recent findings and future directions in the H-Dys field. The H-Dys workshop was instrumental in promoting interactions between basic science and clinical investigators. It also allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families. Future advances in H-Dys research will depend on a novel multi-system approach by investigators from different medical disciplines, and it is hoped that towards a common goal, novel "bench-to-bedside" therapeutics will be developed to improve the lives of, or even cure, patients suffering from dysautonomic syndromes.

Animals↗